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Clinical Policy Bulletin: Antibody Tests for Neurologic Diseases
Revised February 2015
Number: 0340
Policy
I. Aetna considers antibody tests medically necessary for the diagnosis and
treatment of paraneoplastic neurologic disorders when all of the following
are met:
A. The member displays clinical features of the paraneoplastic
neurologic disease in question, and
B. The result of the test will directly impact the treatment being delivered
to the member, and
C. After history, physical examination, and completion of conventional
diagnostic studies, a definitive diagnosis remains uncertain, and one
of the following antibodies is suspected:
Anti-AChR
Anti-amphiphysin Anti-Ri (ANNA-2)
Anti-bipolar cells of the retina Anti-Tr
Anti-CV2/CRMP5 Anti-VGCC
Anti-Hu (ANNA-1) Anti-VGKC
Anti-Ma (MA1, MA2) (Anti-Ta) Anti-Yo (APCA-1)
Anti-recoverin Anti-nAChR
II. Aetna considers antibody tests medically necessary for the diagnosis and
treatment of neurologic diseases when all of the following are met:
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A. The member displays clinical features of the neurologic disease in
question, and
B. The result of the test will directly impact the treatment being delivered
to the member, and
C. After history, physical examination, and completion of conventional
diagnostic studies, a definitive diagnosis remains uncertain, and one
of the following antibodies is suspected:
Anti-AChR
Anti-asialo-GM1 Anti-GT1a
Anti-GM1 Anti-La
Anti-GM2 Anti-MAG
Anti-GAD Anti-MUSK
Anti-GD1a Anti-Ro
Anti-GD1b Anti-sulfatide
Anti-GQ1b Anti-VGCC
III. Aetna considers the LEMS antibody test to detect antibodies to the P/Q
VGCC medically necessary in confirming the diagnosis of Lambert-Eaton
myasthenic syndrome when the clinical features and electrophysiology
studies are inconclusive in diagnosing Lambert-Eaton myasthenic
syndrome.
IV. Aetna considers NMO-IgG autoantibody medically necessary distinguish
neuromyelitis optica from multiple sclerosis.
V. Aetna considers antibody tests for screening of neurologic
diseases experimental and investigational. These tests are only considered
medically necessary when ordered selectively for evaluating persons with
signs and symptoms of specific immune-mediated neuromuscular
conditions.
VI. Aetna considers auto-antibodies (Abs) (e.g., aquaporin 4 (AQP4)-Ab,
glycine receptor Abs (GlyR-Ab), myelin oligodendrocyte glycoprotein (MOG)
-Ab, N-methyl-D-aspartate receptor (NMDAR)-Ab, and voltage-gated
potassium channel (VGKC)-complex Abs) testing for the diagnosis of
childhood-acquired demyelinating syndromes experimental and
investigational.
VII. Aetna considers aquaporin-4 autoantibodies testing for the diagnosis of
recurrent optic neuritis or chronic relapsing inflammatory neuropathy
experimental and investigational because the effectiveness of this approach
has not been established.
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See also CPB 0285 - Plasmapheresis/Plasma Exchange/Therapeutic Apheresis
and CPB - 0206 Parenteral Immunoglobulins.
Background
Autoantibodies to nervous system components have been detected in patients with
neurologic symptoms such as paresthesias, weakness, and twitching. Many
autoantibodies have been discovered and characterized; however, research is
ongoing in the field of neuroimmunology and there remains a paucity of clinical
trials in the peer-reviewed medical literature describing their usefulness in clinical
practice. In a review on the use of autoantibodies as predictors of disease,
Scofield (2004) stated that long-term large studies of outcome are needed to
assess the use of assaying autoantibodies for prediction of disease. A review of
laboratory testing in peripheral nerve disease indicated that the use of antibody
assays should be very selective and should not be used as "screening" studies.
Antibody testing often produces results that can be confusing; thus, a stepwise and
directed approach to the evaluation of peripheral neuropathy utilizing clinical
examination and electrodiagnostic testing can increase the yield of finding a
treatable cause (Chang, 2002).
Antibodies to Glycolipid and Glycoprotein-Related Saccharides (MAG, GM1, Asialo
-GM1 (Anti-GA1), GD1a, GD1b, GQ1b, MAG-SGPG, Sulfatide) (See Appendix for
Complete List)
Gangliosides are a group of glycosphingolipids widely distributed in membrane
components of the nervous system. They possess a common long chain fatty acid,
but exhibit distinctive carbohydrate moieties containing one or more sialic acid
residues. Ganglioside nomenclature is defined by the following scheme: (i) G
refers to ganglio; (ii)
M, D, T, and Q refer to the number of sialic acid residues (mono, di, tri, and quad);
and (iii) numbers and lower case letters refer to the sequence of migration on thin
layer chromatography. The gangliosides most commonly recognized by
neuropathy associated autoantibodies are GM1, asialo-GM1, GD1a, GD1b, and
GQ1b.
Chronic immune-mediated polyneuropathies in which the peripheral nerves are
selectively affected include chronic inflammatory demyelinating polyneuropathy
(CIDP), demyelinating polyneuropathy associated with IgM anti-myelin-associated
glycoprotein (anti-MAG)) antibodies or anti-sulfoglucuronyl paragloboside (anti-
SGPG) antibodies, multi-focal motor neuropathy associated with IgM anti-
ganglioside M1 (anti-GM1) or anti-GD1a antibodies, and sensory polyneuropathy
associated with IgM anti-sulfatide antibodies or anti-GD1b or disialosyl ganglioside
antibodies. Some of these autoantibodies also occur as IgM monoclonal
gammopathies in patients with non-malignant monoclonal gammopathies.
Detection of ganglioside M1 (GM1) antibody, usually of the IgM isotype, is
associated with multi-focal motor neuropathy and lower motor neuropathy,
characterized by muscle weakness and atrophy. Multi-focal motor neuropathy may
occur with or without high serum titers of anti-GM1 antibodies. GM1 antibodies are
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detected in approximately 50 % of persons with multi-focal motor neuropathy (Tidy,
2007). However, whether the presence of anti-GM1 antibody or its titer has any
bearing on the response to therapy is controversial (Sridharan and Lorenzo, 2002).
GM1 antibodies of the IgG and IgA isotypes may be found in association with
amyotrophic lateral sclerosis (ALS). European Federation of Neurological
Societies (EFNS) guidelines (2006) on amyotrophic lateral sclerosis recommend
testing for anti-GM1, as well as anti-MAG and anti-Hu antibodies (see below) in
selected cases.
Ganglioside glycolipid antibodies may be associated with different forms or aspects
of Guillain-Barre Syndrome (GBS). Increased titers of IgG anti-GM1 or GD1a
ganglioside antibodies have been associated with GBS and acute motor axonal
neuropathy, and may be useful in persons suspected of having these syndromes.
Antibodies to GM1 and GD1a are mostly associated with axonal variants of GBS.
Antibodies to GT1a are associated with swallowing dysfunction. The GD1b
ganglioside is present in peripheral nerves on the surface of sensory neurons in the
dorsal root ganglion. Antibodies to GD1b are associated with pure sensory GBS.
Increased IgG anti-GQ1b ganglioside antibodies are closely associated with the
Miller-Fisher syndrome, and may be useful in the evaluation of patients suspected
of having this syndrome. Antibodies against GQ1b are found in 85 to 90 % of
patients with the Miller Fisher syndrome, characterized by ataxia, areflexia, and
ophthalmoplegia. In clinical practice, commercially available testing for serum IgG
antibodies to GQ1b is useful for the diagnosis of Miller Fischer syndrome, having a
sensitivity of 85 to 90 %. GQ1b antibodies are also found in GBS patients with
ophthalmoplegia, but not in GBS patients without ophthalmoplegia. Antibodies to
GQ1b may also be present in Bickerstaff encephalitis and the pharyngo-cervical
brachial GBS variant, but not in disorders other than GBS.
Myelin-associated glycoprotein (MAG) is a constituent of peripheral and central
nervous system myelin. High titer IgM antibodies to MAG are associated with
sensorimotor demyelinating peripheral neuropathy, and are associated with
multiple sclerosis, myasthenia gravis, and systemic lupus erythematosus (SLE)
(Tidy, 2007).
Antibodies recognizing MAG react with a carbohydrate determinant that is also
present on SGPG. Initial assays for MAG antibody utilized SGPG as the target
antigen. However, some laboratories now perform 2 separate enzyme-linked
immunosorbant assay (ELISA) procedures, one utilizing SGPG as antigen and one
utilizing the entire MAG as antigen, to maximize detection of MAG antibodies.
Researchers are currently examining the cross-reacted relationship of IgM binding
to both SGPG and MAG and their significance in neuropathy (Garces-Sanchez,
2008).
MAG antibodies are usually associated with the presence of an IgM monoclonal
protein; approximately 50 % of patients with IgM monoclonal gammopathies and
associated peripheral neuropathies have detectable MAG antibodies. Detection of
MAG antibodies may be useful in paraprotein demyelinating neuropathies. EFNS
guidelines (2006) state that a causal relationship between a paraprotein and a
demyelinating neuropathy is highly probable if there is an immunoglobulin M (IgM)
paraprotein (monoclonal gammopathy of uncertain significance [MGUS] or
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Waldenstrom's) and there are high titers of anti-MAG or anti-GQ1b antibodies. A
causal relationship is probable in persons with IgM paraprotein (MGUS or
Waldenström's) with high titers of IgM antibodies to other neural antigens (GM1,
GD1a, GD1b, GM2, sulfatide), and slowly progressive predominantly distal
symmetrical sensory neuropathy.
Guidelines from the British Society of Haematology recommend testing for anti-
MAG in persons with Waldenstrom's macroglobulinemia who present with
neurological symptoms (Johnson et al, 2005).
High titers of antibodies to the ganglioside asialo GM1 (anti-GA1) have been
associated with motor or sensorimotor neuropathies. In most cases, these
antibodies cross-react with the structurally related glycolipids GM1 and GD1b,
although specific anti-asialo GM1 antibodies have also been reported (Lopez,
2006). Some individuals with proximal lower motor neuron syndromes (P-LMN) (30
%) have selective serum antibody binding to asialo-GM1 ganglioside; however,
there is no evidence that P-LMN syndromes respond to immunosuppressive
treatment.
Antibodies Associated with Paraneoplastic Syndromes and Associated Cancers
(Anti-Hu, Anti-Yo, Anti-Ri, Anti-VGKC, Anti-VGCC, Anti-CV2, Anti-Ma, Anti-
Amphiphysin, Anti-Zic4) (See Appendix for Complete List)
Paraneoplastic neurologic syndromes are a heterogeneous group of neurologic
disorders associated with systemic cancer and caused by mechanisms other than
metastases, metabolic and nutritional deficits, infections, coagulopathy, or side
effects of cancer treatment. These syndromes may affect any part of the nervous
system from cerebral cortex to neuromuscular junction and muscle, either
damaging one area or multiple areas. Although a pathogenic role of paraneoplastic
antibodies has not been proven, their presence indicates the paraneoplastic nature
of a neurologic disorder, and in many cases, can narrow the search for an occult
tumor to a few organs.
Polyclonal immunoglobulin G (IgG) anti-Hu antibodies (previously called ANNA-1)
are found predominantly in patients with paraneoplastic neurologic syndromes
associated with small-cell carcinoma of the lung. Anti-Hu antibodies are also
expressed in most neuroblastomas and occasional other tumors (including several
types of sarcoma and prostate carcinoma). Anti-Hu antibody reacts with 35- to 42-
kD proteins present in nuclei and cytoplasm of virtually all neurons. The role of Hu
proteins in small-cell lung cancer and the other cancers in which they are
expressed is unclear (Mehdi and Ko, 2002). Some investigators have argued that
detection of anti-Hu antibody is important to determine whether a paraneoplastic
syndrome is immune-mediated and thus, in theory, amenable to
immunosuppressive therapy (Santacroce et al, 2002; Senties-Madrid and Vega-
Boada, 2001). However, the value of immunosuppressive therapy in antibody
associated paraneoplastic syndromes has not been proven in clinical studies.
Although the titer of anti-Hu antibodies has been suggested as a prognostic
indicator of paraneoplastic neurologic syndromes, the clinical course of these
syndromes is unpredictable (Liebeskind, 2001).
Paraneoplastic limbic encephalitis (PLE) is a rare disorder characterized by
personality changes, irritability, depression, seizures, memory loss and sometimes
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dementia. The diagnosis is difficult because clinical markers are often lacking and
symptoms usually precede the diagnosis of cancer or mimic other complications.
Limbic encephalitis may be associated with voltage-gated potassium channel
antibodies (VGKC) (53 %). However, responsiveness to treatment is not limited to
patients with VGKC antibodies (Bataller, 2007). Other paraneoplastic
encephalomyelitis antibodies include anti-CV2, anti-Ma1, anti-Ma2 (anti-Ta, anti-
MaTa), and several other atypical antibodies. The targets of such antibodies may
be quite varied, including neuropil and intraneuronal sites. Testicular cancer is
associated with anti-Ma2 antibodies. The Ma2 antigen is selectively expressed in
neurons and the testicular tumor. Ma2 shares homology with Ma1, a gene that is
associated with other paraneoplastic neurologic syndromes, particularly brainstem
and cerebellar dysfunction. Treatment of the tumor is reported to have more effect
on neurologic outcome than the use of immune modulation (Gultekin, 2000).
The diagnosis of Lambert-Eaton myasthenic syndrome (LEMS) is usually made on
clinical grounds and confirmed by electrodiagnostic studies. A serum test for
voltage-gated calcium channel antibodies (VGCC) is commercially available.
Treatment involves removing the cancer associated with the disease. If cancer is
not found, immunosuppressive medications and acetylcholinesterase inhibitors are
used with moderate success. Patients with idiopathic LEMS should be screened
every 6 months with chest imaging for cancer (Mareska, 2004).
Anti-Yo antibodies (also called Purkinje cell antibody type 1 or PCA-1) primarily
occur in patients with paraneoplastic cerebellar degeneration (PCD) who have
breast cancer or tumors of the ovary, endometrium, and fallopian tube. The target
antigens of anti-Yo antibodies are the cdr proteins that are expressed by Purkinje
cells and ovarian and breast cancers. A cytotoxic T cell response against cdr2 has
also been identified in these patients.
Anti-CV2 antibodies, directed against a cytoplasmic antigen in some glial cells, and
against peripheral nerve antigens, have been associated with several syndromes,
including cerebellar degeneration, limbic encephalitis, encephalomyelitis, peripheral
neuropathy, and optic neuritis. The most common tumors are SCLC, thymoma,
and uterine sarcoma.
Opsoclonus is a disorder of ocular motility characterized by spontaneous,
arrhythmic, conjugate saccades occurring in all directions of gaze without a
saccadic interval. Although opsoclonus can be paraneoplastic in origin, it can also
result from viral infections, post-streptococcal pharyngitis, metabolic disorders,
metastases, and intra-cranial hemorrhage. The most frequent tumor associated
with opsoclonus myoclonus in adults is small cell lung cancer. In women, however,
the detection of anti-Ri (anti-neuronal nuclear autoantibody type 2, or ANNA-2)
usually indicates the presence of breast cancer, although other tumors have been
reported (e.g., gynecologic, lung, bladder). The target antigens of anti-Ri
antibodies are the Nova proteins.
In a cross-sectional study, Pranzatelli et al (2002) examined paraneoplastic
antibodies in 59 children with opsoclonus-myoclonus-ataxia, 86 % of them were
moderately or severely symptomatic, and 68 % of them had relapsed at the time of
testing. This total number of patients includes 18 children with low-stage
neuroblastoma (tested after tumor resection), 6 of them had never been treated
with immunosuppressants. All were sero-negative for anti-Hu, anti-Ri (IgG
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autoantibody ANNA-2), and anti-Yo (antibodies against a Purkinje cell cytoplasmic
antigen, called Yo), the 3 paraneoplastic antibodies most associated with
opsoclonus-myoclonus or ataxia in adults. The findings of this study suggested
that anti-Hu, anti-Ri, and anti-Yo do not explain relapses in pediatric opsoclonus-
myoclonus-ataxia.
Paraneoplastic optic neuritis has been described in a few reports, usually in
association with paraneoplastic encephalomyelitis or retinitis and small cell lung
cancer. Some of these patients harbor antibodies to the 62kDa collapsin-
responsive mediator protein-5 (CRMP-5, also called anti-CV2). However, the small
number of patients, the extensive number of accompanying symptoms, and the
frequent co-occurrence of other antibodies suggest low specificity and sensitivity of
CRMP-5 antibodies as markers of paraneoplastic optic neuritis or retinitis
associated with small cell lung cancer.
Anti-Ro/SSA and anti-La/SSB antibodies, which are directed against two extractable
nuclear antigens, have been detected with high frequency in patients with Sjögren's
syndrome. They also have diagnostic usefulness in patients with SLE. Indications
for ordering an anti-Ro/SSA antibody test include: women with SLE who have
become pregnant; women who have a history of giving birth to a child with heart
block or myocarditis; patients with a history of unexplained photosensitive skin
eruptions; patients suspected of having a systemic connective tissue disease in
whom the screening ANA test is negative; patients with symptoms of xerostomia,
keratoconjunctivitis sicca and/or salivary and lacrimal gland enlargement; and
patients with unexplained small vessel vasculitis or atypical multiple sclerosis.
Retinal antibodies have been associated with small cell carcinoma of the lung
(Tidy, 2007).
In patients with neurologic symptoms of unknown cause, detection of Zic4
antibodies has been associated with cerebellar degeneration and small-cell lung
cancer (SCLC) and often associates with anti-Hu or CRMP5 antibodies (Bataller,
2004). However, there is insufficient evidence on the clinical usefulness of
measuring Zic4 antibodies in the peer-reviewed medical literature.
Stiff-Person Syndrome
Stiff-person syndrome (formerly called stiff-man syndrome) is an uncommon
disorder characterized by progressive muscle stiffness, rigidity, and spasm
involving the axial muscles. The muscle spasms are triggered by different stimuli
and may lead to limb deformities and fracture. Electrophysiological studies show
continuous discharges of motor unit potentials, which improve during sleep or
general anesthesia. Paraneoplastic stiff-person syndrome usually occurs in
patients with breast cancer and small cell lung cancer (SCLC). Paraneoplastic
muscle rigidity in association with myoclonus has also been described in patients
with SCLC and progressive encephalomyelitis. The serum of patients with
paraneoplastic stiff-person syndrome often contains antibodies against a protein
called amphiphysin. In contrast, patients with stiff-person syndrome who do not
have cancer (but who usually develop diabetes and other symptoms of
endocrinopathy) have antibodies against glutamic acid decarboxylase (GAD). Both
GAD and amphiphysin are nonintrinsic membrane proteins that are concentrated in
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nerve terminals, where a pool of both proteins is associated with the cytoplasmic
surface of synaptic vesicles.
To better understand GADAb and SPS, Murinson et al (2004) studied a population
of patients with clinically suspected SPS. A total of 576 patients with suspected
SPS underwent ICC. Of these, 286 underwent RIA for GADAb; 116 were GADAb-
positive by one or both tests. Ninety-six percent of those positive by ICC had RIA
values several standard deviations above normal. RIA did not correlate with age or
illness duration. Marked elevations of RIA for GADAb were characteristic of ICC-
confirmed SPS, and modest elevations were not. The findings of this study
indicated that patients with clinically suspected SPS almost always have either very
high GADAb or undetectable GADAb. An additional important observation was that
the specificity of RIA for GAD-positive SPS is sharply dependent on the diagnostic
cut-off value. The authors noted that until a universal standard for GAD65 RIA is
adopted, interpretation will depend on knowing the particularities of each testing
laboratory.
In an editorial, Chang and Lang (2004) stated that "the data from the Murinson, et
al. do not imply a pathogenic role because they found no correlation between age
or duration of illness and GADAbs and no change over the course of the disease
in individuals. Thus, there is no value in monitoring the antibody titer during the
course of disease .... Although the exact role of GADAbs in the pathogenesis of
SPS still remains elusive, Murinson, et al. have established the reliability of RIA in
measuring these antibodies. Nevertheless, clinical criteria remain the benchmark
for the diagnosis of SPS".
Myasthenia Gravis (MuSk, AChR Antibodies)
Myasthenia gravis (MG), an autoimmune disorder, is caused by the failure of
neuromuscular transmission, which results from the binding of autoantibodies to
proteins involved in signaling at the neuromuscular junction. These proteins
include the nicotinic acetylcholine receptors (AChRs) or, less frequently, a muscle-
specific tyrosine kinase (MuSK) involved in AChRs clustering. Chan and Liu (2005)
noted that diagnosis of MG relies on clinical as well as investigatory evidences.
Among the usual investigatory tools, the Tensilon (edrophonium chloride) test has
been given the credit as a test of high sensitivity (80 to 85 %). Antibodies to
AChRs are found in about 80 % of persons with myasthenia gravis (Tidy, 2007).
Vincent and Leite (2005) noted that some of the 20 % of patients with MG who do
not have antibodies to AChRs have antibodies to MuSK, but a full understanding of
their frequency, the associated clinical phenotype and the mechanisms of action of
the antibodies has not yet been achieved. Moreover, some patients do not
respond well to conventional corticosteroid therapy. These researchers reported
that MuSK antibodies are found in a variable proportion of AChR antibody negative
MG patients who are often, but not exclusively, young adult females, with bulbar,
neck, or respiratory muscle weakness. The thymus histology is normal or only very
mildly abnormal. Surprisingly, limb or intercostal muscle biopsies exhibit no
reduction in AChR numbers or complement deposition. However, patients without
AChR or MuSK antibodies appear to be similar to those with AChR antibodies and
may have low-affinity AChR antibodies. A variety of treatments, often intended to
enable corticosteroid doses to be reduced, have been used in all types of MG with
some success, but they have not been subjected to randomized clinical trials. The
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authors noted that MuSK antibodies define a form of MG that can be difficult to
diagnose, can be life threatening and may require additional treatments. An
improved AChR antibody assay may be helpful in patients without AChR or MuSK
antibodies. Randomized clinical studies of drugs in other neuroimmunological
diseases may help to guide the treatment of MG.
Romi et al (2005) examined MG severity and long-term prognosis in seronegative
MG compared with seropositive MG, and reviewed specifically at anti-AChR
antibody negative and anti-MuSK antibody negative patients. A total of 17
consecutive sero-negative non-thymomatous MG patients and 34 age- and sex-
matched contemporary sero-positive non-thymomatous MG controls were included
in a retrospective follow-up study for a total period of 40 years. Clinical criteria
were assessed each year, and muscle antibodies were assayed. There was no
difference in MG severity between sero-negative and sero-positive MG. However,
when thymectomized patients were excluded from the study at the year of
thymectomy, sero-positive MG patients had more severe course than sero-negative
(p < 0.001). One sero-positive patient died from MG related respiratory
insufficiency. The need for thymectomy in sero-negative MG was lower than in
sero-positive MG. None of the sero-negative patients had MuSK antibodies. The
findings of this study showed that the presence of AChR antibodies in MG patients
correlates with a more severe MG. The authors noted that with proper treatment,
especially early thymectomy for seropositive MG, the outcome and long-term
prognosis is good in patients with and without AChR antibodies.
Lee et al (2006) stated that several reports from Western countries suggest
differences in the clinical features of patients with MuSK antibody-positive and
MuSK antibody-negative sero-negative MG. These investigators performed the
first survey in Korea of MuSK antibodies, studying 23 patients with AChR-antibody
sero-negative MG. MuSK antibodies were present in 4 (26.7 %) of 15 generalized
sero-negative MG patients and none of 8 ocular sero-negative MG patients. All 4
MuSK positive patients were females, with pharyngeal and respiratory muscle
weakness, and required immunosuppressive treatment. However, overall disease
severity and age at onset was similar to that of MuSK-negative MG and treatment
responses were equally good.
In the appropriate clinical setting (lack of AChR-Ab and typical clinical features
listed below), MuSK testing can clarify the diagnosis and perhaps direct treatment.
However, the initial management of clinically apparent myasthenia should be the
same for patients with or without AChR antibodies; this would change only if future
studies find additional therapeutic differences related to MuSK status.
Although some differences between MuSK-positive and MuSK-negative MG have
been found, the initial management of clinically apparent MG should be the same
for patients with or without MuSK antibodies; this would change only if future
studies show significant therapeutic differences related to MuSK status.
GALOP Autoantibody
A peripheral neuropathy syndrome described by Pestronk (1994) is the gait
disorder, autoantibody, late-age onset, polyneuropathy (GALOP) syndrome that
resembles anti-MAG neuropathies with distal sensory loss, ataxia, and
demyelinating features on nerve conduction velosity testing. High titer IgM
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antibodies bind to a central nervous system myelin antigen preparation that
copurifies with MAG. GALOP syndrome appears to be immune-mediated.
However, there is insufficient evidence on the clinical usefulness of measuring the
GALOP autoantibody for the diagnosis and treatment of GALOP syndrome in the
peer-reviewed medical literature.
Finally, it has been estimated that up to 1/3 of peripheral neuropathies are
idiopathic. These neuropathies are classified by their clinical syndrome, which
include sensory axonal polyneuropathy with large and small fiber involvement,
small-fiber sensory neuropathy, large-fiber sensory neuropathy, sensorimotor
neuropathy, and autonomic neuropathy (Shy-Drager syndrome). Treatment is
usually symptomatic, although some patients may respond to a trial of
immunotherapy. More research into their causes as well as the development of
better diagnostic tests and treatments are needed (Chang, 2002).
Dermatomyositis/Polymyositis
Several serological abnormalities (e.g., formation of specific autoantibodies) have
been identified in patients with dermatomyositis (DM) and polymyositis
(PM), however their routine use has not yet been established. As a group, these
antibodies have been termed myositis-specific antibodies (MSAs) and include
antibodies to EJ, Jo-1, Ku, Mi-2, OJ, PL-7, PL-12, signal recognition protein (SRP),
and U2 small nuclear ribonucleoprotein (snRNP). Pappu and Seetharaman (2009)
stated that anti-nuclear antibody assay findings are positive in 1/3 of patients
with PM and in only 15 % of patients with inclusion body myositis, and about 4 % of
patients with PM have antibodies to SRPs. Miller (2009) noted that
electromyography (EMG) and tissue biopsies of skin and/or muscle are important
facets of the evaluation of patients with possible DM or PM. Abnormalities in EMG
may support the diagnosis of DM or PM but are not diagnostic. Moreover, skin
biopsy (e.g., findings of Gottron's sign, the shawl sign, and erythroderma) can
provide confirmation of the diagnosis of DM. In addition, muscle biopsy is the
definitive test for PM, in which skin lesions are not seen.
Although MSA may offer valuable information regarding prognosis and potential
future patterns of organ involvement, there is no reliable evidence that detection of
these antibodies influences clinical management. Furthermore, while there is some
limited evidence on the association between the presence of MSA with cancer-
associated myositis (CAM), the available literature on this association is limited.
Chinoy et al (2007) stated that these antibody tests are not foolproof, and do not
replace the need for intensive surveillance for cancer in persons with new onset
myositis. The authors concluded that before these results can be applied clinically,
confirmation in a large independent trial with prospective follow-up is needed.
Kalluri et al (2009) stated that the anti-synthetase syndrome consists of interstitial
lung disease (ILD), arthritis, myositis, fever, mechanic's hands, and Raynaud
phenomenon in the presence of an anti-synthetase autoantibody, most commonly
anti-Jo-1. It is believed that all the anti-synthetases are associated with a similar
clinical profile, but definitive data in this diverse group are lacking. These
researchers examined the clinical profile of anti-PL-12, an anti-synthetase
autoantibody directed against alanyl-transfer RNA synthetase. A total of 31
subjects with anti-PL-12 autoantibody were identified from the databases at the
Medical University of South Carolina, the University of Pittsburgh Medical Center,
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Johns Hopkins Medical Center, and Brigham and Women's Hospital. The medical
charts were reviewed and the following data were recorded: demographic
information; pulmonary and rheumatological symptoms; connective tissue disease
(CTD) diagnoses; serological autoantibody findings; CT scan results; BAL findings;
pulmonary function test results; lung histopathology; and treatment interventions.
The median age at symptom onset was 51 years; 81 % were women and 52 %
were African American; 90 % of anti-PL-12-positive patients had ILD, 65 % of
whom presented initially to a pulmonologist; 90 % of anti-PL-12-positive patients
had an underlying CTD. Polymyositis and DM were the most common underlying
diagnoses. Raynaud phenomenon occurred in 65 % of patients, fever in 45 % of
patients, and mechanic's hands in 16 % of patients. Test results for the presence
of antinuclear antibody were positive in 48 % of cases. The authors concluded that
anti-PL-12 is strongly associated with the presence of ILD, but less so with myositis
and arthritis.
Derfuss and Meinl (2012) stated that identification of auto-antigens in demyelinating
diseases is essential for the understanding of the pathogenesis. Immune responses
against these antigens could be used as biomarkers for diagnosis, prognosis and
treatment responses. Knowledge of antigen-specific immune responses in
individual patients is also a prerequisite for antigen-based therapies. A proportion of
patients with demyelinating disease have antibodies to aquaporin 4 (AQP4) or
myelin oligodendrocyte glycoprotein (MOG). Patients with anti-AQP4 have the
distinct clinical presentation of neuromyelitis optica (NMO), and these patients often
also harbor other autoimmune responses. In contrast, anti- MOG is seen in patients
with different disease entities such as childhood multiple sclerosis (MS), acute
demyelinating encephalomyelitis (ADEM), anti-AQP4
negative NMO, and optic neuritis, but hardly in adult MS. A number of new
candidate auto-antigens have been identified and await validation. Antigen-based
therapies are mainly aimed at tolerizing T-cell responses against myelin basic
protein (MBP) and have shown only modest or no clinical benefit so far. The
authors concluded that currently, only few patients with demyelinating diseases can
be characterized based on their auto-antibody profile. The most prominent
antigens in this respect are MOG and AQP4. Moreover, they stated that further
research has to focus on the validation of newly discovered antigens as
biomarkers.
Reindl et al (2013) noted that MOG has been identified as a target of demyelinating
auto-antibodies in animal models of inflammatory demyelinating diseases of the
central nervous system (CNS), such as MS. Numerous studies have aimed to
establish a role for MOG antibodies in patients with MS, although the results have
been controversial. Cell-based immunoassays using MOG expressed in
mammalian cells have demonstrated the presence of high-titer MOG antibodies in
pediatric patients with ADEM, MS, AQP4-seronegative NMO, or isolated optic
neuritis (ON) or transverse myelitis (TM), but only rarely in adults with these
disorders. These studies indicated that MOG antibodies could be associated with a
broad spectrum of acquired human CNS demyelinating diseases. The authors
discussed the current literature on MOG antibodies, their potential clinical
relevance, and their role in the pathogenesis of MOG antibody-associated
demyelinating disorders.
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Hacohen and colleagues (2014) noted that auto-antibodies to glial, myelin and
neuronal antigens have been reported in a range of central demyelination
syndromes and autoimmune encephalopathies in children, but there has not been
a systematic evaluation across the range of CNS autoantibodies in childhood-
acquired demyelinating syndromes (ADS). Children under the age of 16 years with
first-episode ADS were identified from a national prospective surveillance study;
serum from 65 patients had been sent for a variety of diagnostic tests. Antibodies
to astrocyte, myelin and neuronal antigens were tested or re-tested in all samples.
A total of 15 patients (23 %) were positive for at least 1 antibody (Ab): AQP4-Ab
was detected in 3 (2 presenting with NMO and 1 with isolated ON); MOG-Ab was
detected in 7 (2 with ADEM, 2 with ON, 1 with TM and 2 with clinically isolated
syndrome [CIS]). N-Methyl-D-Aspartate receptor (NMDAR)-Ab was found in 2 (1
presenting with ADEM and 1 with ON). Voltage-gated potassium channel (VGKC)-
complex antibodies were positive in 3 (1 presenting with ADEM, 1 with ON and 1
with CIS). Glycine receptor antibody (GlyR-Ab) was detected in 1 patient with TM.
All patients were negative for the VGKC-complex-associated proteins LGI1,
CASPR2 and contactin-2. The authors concluded that a range of CNS-directed
autoantibodies were found in association with childhood ADS. Moreover, they
stated that although these antibodies are clinically relevant when associated with
the specific neurological syndromes that have been described, further studies are
needed to evaluate their roles and clinical relevance in demyelinating diseases.
Furthermore, an UpToDate review on “Differential diagnosis of acute central
nervous system demyelination in children” (Lotze, 2014) states that “Differential
diagnostic considerations for acute central nervous system demyelination in
children include acute disseminated encephalomyelitis (ADEM), multiple sclerosis
(MS), optic neuritis, transverse myelitis, neuromyelitis optica (Devic disease), and
various infectious, metabolic, and rheumatologic conditions. Most of these
conditions are thought to be caused by immune system dysregulation triggered by
an infectious agent in a genetically susceptible host. With the possible exception of
the NMO-IgG autoantibody found in neuromyelitis optica, there are no disease-
specific biomarkers for these conditions, making it difficult to distinguish among
them at the time of the initial presentation. However, certain clinical features,
laboratory results, and imaging findings can usually lead to the correct diagnosis”.
Aquaporin-4 Autoantibodies Testing for the Dagnosis of Recurrent Optic Neuritis or
Chronic Relapsing Inflammatory Neuropathy
Waschbisch et al (2013) stated that recurrent optic neuritis is frequently observed in
multiple sclerosis (MS) and is a typical finding in NMO. Patients that lack further
evidence of demyelinating disease are diagnosed with RION (recurrent isolated
optic neuritis) or CRION (chronic relapsing inflammatory neuropathy) if they require
immunosuppressive therapy to prevent further relapses. The etiology and disease
course of this rare condition are not well-defined. These investigators studied a
series of 10 patients who presented with recurrent episodes of isolated optic
neuritis (ON, n = 57) and were followed over a median of 3.5 years. Visual acuity
was severely reduced at the nadir of the disease (20/200 to 20/800). All patients
had MRI non-diagnostic for MS/NMO and were aquaporin-4 antibody negative. Six
patients fulfilled the CRION criteria. In 2 of these a single ON followed by a long
disease-free interval preceded development of CRION for years, suggesting the
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conversion of an initially "benign" isolated ON into the chronic relapsing course.
Cerebrospinal fluid (CSF) analysis revealed mild pleocytosis in 5 patients, identical
oligoclonal bands in serum and CSF were observed in 2 patients, while the others
remained negative. The authors concluded that recurrent ON is a disease entity
that requires aggressive glucocorticoid and eventually long-term
immunosuppressive therapy to prevent substantial visual impairment.
Petzold and Plant (2014) noted that CRION is an entity that was described in
2003. Early recognition of patients suffering from CRION is relevant because of
the associated risk for blindness if treated inappropriately. These researchers
performed a systematic literature review, irrespective of language, on CRION.
They retrieved 22 case series and single reports describing 122 patients with
CRION between 2003 and 2013. They reviewed the epidemiology, diagnostic work
-up, differential diagnosis, and treatment (acute, intermediate, and long-term) in
view of the collective data. These data suggested that CRION is a distinct
nosological entity, which is sero-negative for anti-aquaporin-4 autoantibodies and
recognized by and managed through its dependency on immuno-suppression.
Also, an UpToDate review on “Optic neuropathies” (Osborne and Balcer, 2015)
does not mention aquaporin-4 autoantibodies testing as a management tool.
Appendix
Table 1: Disorders Associated with Antibodies to Glycolipid and Glycoprotein-
Related Saccharides:
Neuropathy
Syndrome
Antibody Target Antibody
Isotype
Chronic
Sensory-Motor
Demyelinating
Myelin-associated
glycoprotein (MAG)
Other: SGPG
IgM (monoclonal)
Chronic ataxic
neuropathy
GD1b, GQ1b IgM (monoclonal)
Motor neuropathy GM1 IgM (polyclonal or
monoclonal)
Sensory neuropathy Sulfatide IgM (monoclonal
or polyclonal)
Acute motor axonal
neuropathy
GM1, GD1a IgG
Miller Fisher syndrome
Bickerstaff's brainstem
encephalitis
Acute
ophthalmoparesis
Ataxic Guillain-Barré
syndrome
GQ1b, GT1a IgG
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Pharyngeal-cervical-
brachial weakness
GT1a (GQ1b) IgG
Adapted from: Pestronk, 2008.
Table 2: Antibodies Associated with Paraneoplastic Syndromes and Associated
Cancers:
Antibody Syndrome Associated
Cancers
Well characterized paraneoplastic antibodies*
Anti-Hu
(ANNA-1)
Paraneoplastic
encephalomyelitis including
cortical, limbic, brainstem
encephalitis; paraneoplastic
cerebellar degeneration,
myelitis; paraneoplatic sensory
neuronopathy, and/or autonomic
dysfunction
SCLC, other
Anti-Yo
(APCA-1)
Paraneoplastic cerebellar
degeneration
Gynecological,
breast
Anti-Ri
(ANNA-2)
Paraneoplastic cerebellar
degeneration, brainstem
encephalitis, opsoclonus-
myoclonus
Breast,
gynecological,
SCLC,
Hodgkin's
lymphoma
Anti-Tr Paraneoplastic cerebellar
degeneration
SCLC,
thymoma, other
Anti-
CV2/CRMP5
Paraneoplastic
encephalomyelitis,
paraneoplastic cerebellar
degeneration, chorea,
peripheral neuropathy
Germ-cell
tumors of testis,
lung cancer,
other solid
tumors
Anti-Ma
proteins
(Ma1, Ma2)
***
Limbic, hypothalamic, brainstem
encephalitis (infrequently
paraneoplastic cerebellar
degeneration)
Breast,
testicular, other
Anti-
amphiphysin
Stiff-person syndrome,
paraneoplastic
encephalomyelitis
SCLC
Anti-
recoverin
Cancer-associated retinopathy
(CAR)
Partially-characterized paraneoplastic antibodies**
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Anti-Zic 4 Paraneoplastic cerebellar
degeneration
SCLC
mGluR1 Paraneoplastic cerebellar
degeneration
Hodgkin's
lymphoma
ANNA-3 Paraneoplastic sensory
neuronopathy, paraneoplastic
encephalomyelitis
SCLC
PCA2 Paraneoplastic
encephalomyelitis,
paraneoplastic cerebellar
degeneration
SCLC
Anti-bipolar
cells of the
retina
Melanoma-associated
retinopathy (MAR)
Melanoma
Antibodies that occur with and without cancer association
Anti-VGCC Lambert-Eaton myasthenic
syndrome,
paraneoplastic cerebellar
dysfunction
SCLC
Anti-AChR Myasthenia gravis Thymoma
Anti-VGKC Neuromyotonia, limbic
encephalitis, seizures
Thymoma,
others
nAChR Subacute pandysautonomia SCLC, others
Key: AChR: acetylcholine receptor; APCA: anti-Purkinje cell antibody; ANNA: anti-
neuronal-nuclear antibody; SCLC: small-cell lung cancer; VGCC: voltage-gated
calcium channel; VGKC: voltage-gated potassium channel; nAChR: ganglionic
nicotinic acetylcholine receptor antibodies.
* Well-characterized antibodies are those directed against antigens whose
molecular identity is known, or that have been identified by several investigators.
** Partially-characterized antibodies are those whose target antigens are unknown
or require further analysis in groups of individuals serving as controls.
*** Antibodies to Ma2: younger than 45 years, usually men with testicular germ-cell
tumors; older than 45, men or women with lung cancer and less frequently other
tumors. Ma1 antibodies often associated with tumors other than germ-cell
neoplasms and confers a worse prognosis, with more prominent brainstem and
cerebellar dysfunction.
Adapted from: Dalmau and Rosenfeld, 2006; Bataller and Dalmau, 2004.
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CPT Codes / HCPCS Codes / ICD-9 Codes
Other CPT codes related to the CPB:
83516 Immunoassay for analyte other than infectious agent antibody
or infectious agent antigen; qualitative or semiquantitative,
multiple step method [NMO-IgG autoantibody test]
83519 Immunoassay, analyte, quantitative; by radiopharmaceutical
technique (eg, RIA) [LEMS antibody test]
83520 not otherwise specified
84182 Protein, Western Blot, with interpretation and report, blood or
other body fluid, immunological probe for band identification,
each
84238 Receptor assay; non-endocrine (specify receptor)
86235 Extractable nuclear antigen, antibody to, any method (e.g.,
nRNP, SS-A, SS-B, Sm, RNP, Sc170, J01), each antibody
86255 Fluorescent noninfectious agent antibody; screen, each
antibody [LEMS antibody test]
ICD-9 codes not covered for indications listed in the CPB (not all-
inclusive):
340 Multiple sclerosis
341.0 Neuromyelitis optica
341.1 Schilder's disease
341.20 -
341.22
Acute and idiopathic (transverse) myelitis
341.8 - 341.9 Other and unspecified demyelinating diseases of central
nervous system
357.0 Acute infective polyneuritis
V80.01 -
V80.09
Special screening for neurological conditions
Other ICD-9 codes related to the CPB:
358.00 -
358.01
Myasthenia gravis
358.30 -
358.39
Lambert-Eaton syndrome
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69. Osborne B, Balcer LJ. Optic neuropathies. UpToDate Inc., Waltham, MA.
Last reviewed January 2015.
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